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Repression of Hepatocyte Nuclear Factor 4 by Tumor Suppressor p53: Involvement of the Ligand-Binding Domain and Histone Deacetylase Activity

Environmental Toxicology Graduate Program (Y.M.), Departments of Cell Biology and Neuroscience (S.D.S., F.M.S.) and Biochemistry (G.W., X.L.), University of California, Riverside, California 92521

Address all correspondence and requests for reprints to: Frances M. Sladek, Ph.D., Department of Cell Biology and Neuroscience, 5429 Boyce Hall, University of California, Riverside, Riverside, California 92521.

Tumor suppressor p53 is known to inhibit transactivation by certain nuclear receptors, and overexpressed p53 is known to correlate with poor differentiation in liver cancer. Therefore, we investigated whether wild-type p53 might also affect the function of hepatocyte nuclear factor 41 (HNF41), an orphan receptor required for liver differentiation. Our results show that HNF41-mediated transactivation is repressed by p53 but that the mechanism of repression is not due to inhibition of HNF41 DNA binding. Rather, transfections with Gal4 fusion constructs indicate that the repression is via the ligand-binding domain of HNF41. Furthermore, we found that p53 in human embryonic kidney whole-cell extracts preferentially bound the ligand-binding domain of HNF41 and that the activation function 2 region was required for the binding. Competition for coactivator CREB binding protein could not entirely account for the repression but trichostatin A, an inhibitor of histone deacetylase activity, could reverse p53-mediated repression of HNF41. In contrast, p53-mediated repression of transcriptional activation of the same promoter by another transcriptional activator, CCAAT/enhancer-binding protein-, could not be reversed by the addition of trichostatin A. These results suggest that p53, like other transcriptional repressors, inhibits transcription by multiple mechanisms, one of which involves interaction with the ligand-binding domain and recruitment of histone deacetylase activity.

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